Selective C‐7 Functionalization of Phenanthridines by Microwave‐Assisted Claisen Rearrangements of 8‐Allyloxyphenanthridines

Abstract Carbon‐carbon bond formation in the phenanthridine 7‐position was achieved by microwave‐assisted Claisen rearrangement of 8‐allyloxyphenanthridines. The reactions took place with excellent regioselectivity and high chemical yields. If the 7‐position was substituted, rearrangement to C‐9 took place, but the reaction occurred less readily. Rearrangements of 8‐allyloxy‐5,6‐dihydrophenanthridines (phenanthridines with a saturated B‐ring) gave a mixture of 7‐ and 9‐substituted products. The experimental results were supported by DFT (density functional theory) calculations.


Introduction
The phenanthridine skeleton ( Figure 1) is found in a wide variety of interesting compounds including natural products, (especially Amaryllidaceae alkaloids [1] ) and synthetic molecules. [2] Several phenanthridines are of medicinal interest, for instance as anticancer agents, [3] anti-infectives, [4] anti-diabetes- [5] and antivitiligo compounds [6] as well as PET tracers. [7] There are many examples of late stage CÀ H functionalization and CÀ C bond formation reactions in the phenanthridine 6position, which resembles the 2-position in quinolines, [8] and to some extent also in the phenanthridine 4-position (equivalent to C-8 in quinoline). [8][9] Examples of such reactions elsewhere in the phenanthridine A-ring [10] or in the C-ring [11] are, however, quite limited. The only reports on CH functionalization and CÀ C bond formation in the phenanthridine 7-position, to date, are two examples of transition-metal-catalyzed phenylation of phenanthridin-6(5H)-one, [11a,b] and, in the 9-position, some carbon substituents (tert-butyl, cyclohexyl and 1-adamantyl) have been introduced, generally in moderate yields, by a Minisci-type reaction. [11c] The latter reactions also required a rather bulky substituent at C-6.
We have developed a synthetic route to phenanthridines with a microwave-mediated IMDAF reaction of allylamino-orthofurylarenes as a key-step. [12] Later, we showed that propargylamino-ortho-furylarenes cyclized to 8-hydroxyphenanthridines. [13] The hydroxyl group in the 8-position offers possibilities for further functionalization in the C-ring. We have previously demonstrated that the phenanthridinols can be transformed into the corresponding triflates and C-substituents can be introduced at C-8 by subsequent Suzuki cross-couplings. [13] An oxygen substituent also opens the possibility for late-stage functionalization of the neighboring unsubstituted positions. We herein report on the regioselective Claisen rearrangement [14] of 8allyloxyphenanthridines.

Results and Discussion
Uncatalyzed Claisen rearrangements often require high reaction temperatures and extended reaction times. The use of microwave irradiation may shorten the reaction times substantially and thus eliminates problems with decomposition of starting material and/or product. [14c] We first synthesized the allyloxyphenanthridine 2 a from the phenanthridinol 1 a [13] and subjected it to a microwave-assisted Claisen rearrangement in N,N-diethylaniline following a procedure for rearrangement of simpler allyloxyarenes [15] (Scheme 1, Table 1, entries 1-3).
Even though full conversion of the starting material was achieved ( Table 1, entry 3), the yield of the isolated product was modest, most probably due to loss of the weakly basic compound 3 a during extractions with acid in order to remove the basic and high-boiling solvent. When the solvent was changed to toluene, the work-up could be simplified to removal of the solvent and compound 3 a was isolated in an excellent yield.
The Claisen rearrangement could, in theory, have proceeded to give the 7-allylphenanthridine 3 a or the 9-substituted isomer, but the reaction turned out to be highly regioselective. The only allyl derivative identified in the crude product NMR spectrum was the 7-substituted compound 3 a. One characteristic feature in the 1 H NMR spectrum of 3 a was the relatively large coupling (J = 8.9 Hz) between two aromatic protons; the vicinal hydrogens in the phenanthridine 9-and 10-position (Scheme 1). The position of the allylic substituent in compound 3 a was also supported by HMBC spectroscopy.
Having found efficient conditions for regioselective rearrangement of the allyl ether 2 a, we synthesized a series of 8allyloxyphenanthridines 2 and subjected them to the microwaveassisted Claisen rearrangement (Scheme 2, Table 2).
The ethers 2 were formed in high yields and they generally selectively rearranged to give the corresponding 7-allylphenanthridin-8-ols 3 ( Table 2, entries 1-4 and 14). However, no rearrangement product was formed when the dimethylallyl ether 2 e was subjected to the same reaction conditions. Here, extensive deallylation took place and the phenol 1 a was isolated in 85 % yield ( Table 2, entry 5). The choice of solvent (PhMe or MeCN, Table 2, entries 6 and 7) did not seem to have a significant impact on the outcome. When the reaction temperature was lowered and/or the reaction time shortened, no reaction took place at all (Table 2, entries 7-12). A similar phenomenon has been observed earlier during Claisen rearrangements of prenyloxycoumarins. [16] Rearrangement products of such dimethylallyl ethers tended to quickly undergo a consecutive Cope rearrangement to the para-position after the initial Claisen reaction. If the para-position was blocked, like in our desired product 3 e, elimination of the isoprene fragment from the Claisen product was observed. This was attributed to steric congestion. [16] In the rearrangement of compound 2 f, minor amounts (5 %) of the cyclized product 4 ( Figure 2) were also isolated. The 1 H NMR spectrum of the crude product showed that the cyclization took place during the reaction and not on the weakly acidic silica flash chromatography column. Cyclization of Claisen rearrangement products from β-methylallyl aryl ethers has been observed before. [17] The Claisen rearrangements described above took place with excellent regioselectivity and only formation of 7-allyl phenanthridinols 3 could be observed. Thus, we synthesized the 8allyloxyphenanthridine 2 h where the 7-position was occupied by a methyl substituent and subjected this compound to the same set of rearrangement conditions (Scheme 3). The reaction was substantially slower, and even after 240 min, 18 % unconverted Yield 3 a (%) [b]   Compound 4 (Figure 2) was also isolated (5 %).
starting material 2 h were recovered. Furthermore, significant deallylation took place to give compound 1 d (36 %) and the Claisen rearrangement product 5 a was isolated in ca. 40 % yield together with minor amounts of an unidentified side product. However, it is worth remembering that other methods for latestage CH functionalization at C-9 are very limited. [11c] Finally, we wanted to examine the reactivity and regioselectivity of Claisen rearrangements of phenanthridines with a nonaromatic B-ring (for definition of B-ring, see Figure 1). 5,6-Dihydrophenanthridines with a free NH group are prone to oxidation to the corresponding fully aromatic phenanthridines.
[12b] Therefore, we synthesized the more stable N-methyldihydrophenanthridines 10 from the known compound 6 [12b] (Scheme 4). When the allyloxydihydrophenanthridines 10 a and 10 b were heated in the microwave oven, the starting materials were consumed, but the Claisen rearrangements were rather unselective, leading to the formation of a substantial amount of both isomers 11 and 12. (Scheme 4, Table 3, entries 1 and 2). Furthermore, oxidation in the B-ring, leading to the phenanthridinones 13 and/or 14, also took place. It is worth nothing that C-6 oxidized side products were observed only from C-7 substituted products 11. As discussed below, an electronwithdrawing "meta" substituent favors rearrangement to C-7 over C-9, and the C-6 oxidation may have taken place before the rearrangement. In case of the starting material 10 b, both phenanthridinones 13 b and 14 b were most probably observed, but, what was believed to be compound 13 b was never isolated in pure form. Why apparently only the phenanthridinone 13 b, but not the dihydrophenanthridines 11 b or 12 b, cyclized is somewhat difficult to explain, but may be attributed to a through-space stabilization of the carbocation required for   Yield (%) 11 [b] Yield (%) 12 [b] Yield (%) 13 [b] Yield (%) 14 [b]  cyclization by the lone pair of electrons of the C-6 carbonyl moiety. [18] It has been reported that the regiochemical outcome from Claisen rearrangements of meta-substituted allyloxybenzene derivatives can be predicted from the preferential reactant ground state conformation or the less energetic transition state, or both. [19] In order to shed more light on our experimental findings, DFT calculations at the B3LYP/def2-TZVP level of starting materials, transition states and intermediates level were performed. These calculations showed that, for both the allyloxyphenanthridine 2 a and the dihydro analog 10 a, the conformations leading to the two possible rearrangement products were very close in energy (Figures 3 and 4). However, in case of the fully aromatic substrate 2 a the transition state leading to the observed 7-substituted phenanthridinol 3 a was considerably lower in energy compared to the transition state leading to the not-observed 9-substituted isomer (Figure 3). On the other hand, the dihydro analog 10 a rearranged with relatively low selectivity and here the energy difference between the two transition states was found to be small (Figure 4). The aromatic B-ring in compounds 2 resembles an electron-withdrawing (C=N) meta substituent relative to the allyloxy side chain. It has been reported earlier that electron-withdrawing meta substituents on simple allyloxyarenes tend to favor Claisen rearrangements towards the ortho position, relative to the meta substituent, whereas electron-donating meta substituents favor rearrangements in the opposite direction. [20]

Conclusions
We have shown that readily available 8-allyloxyphenanthridines undergo a Claisen rearrangement to give the corresponding 7allyl-8-hydroxy isomers with excellent regioselectivity. If C-7 was substituted, rearrangement to C-9 took place, but the reaction was considerably slower. Rearrangements of 8-allyloxy-5,6-dihydrophenanthridines gave a mixture of 7-and 9-substituted dihydrophenanthridin-8-ols. The experimental results were supported by DFT calculations and are in line with prior observations for Claisen rearrangements of simple allyloxyarenes. The chemistry described herein provides an efficient methodology for CÀ C bond formation of phenanthridines unsubstituted at the C-7 position. As the only reported examples of CÀ H functionalization and CÀ C bond formation in the phenanthridine 7-position are two examples of transition-metal-catalyzed phenylation of phenanthridin-6(5H)-one, [11a,b] our findings expand the synthetic toolbox for this interesting compound class.

Experimental Section
General procedure for the synthesis of 8-allyloxyphenanthridines 2. Compound 1 (0.19 mmol) and K 2 CO 3 (53 mg, 0.38 mmol) in dry DMF (10 mL) was stirred under argon for 15 min, before the allylic bromide (0.38 mmol) was added. After stirring for additional 75 min, water (25 mL) was added and the resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried (MgSO 4 ), filtered through a plug of silica gel, eluting with hexanes (200 mL) and then EtOAc (250 mL) and the eluents was evaporated in vacuo.
General procedure for the synthesis of 7-allylphenanthridin-8-ols 3. A 0.2-0.3 m solution of compound 2 in toluene under argon was stirred at 250°C for 45 min in the microwave reactor. The mixture was evaporated in vacuo and the product was purified by flash chromatography on silica gel eluting with CH 2 Cl 2 À EtOAc-hexanes (1 : 3 : 36).

Supporting Information Summary
Additional references are cited within the Supporting Information. [21][22][23][24][25][26][27] The Supporting Information contains description of DFT calculations and procedures and spectral data for all novel compounds as well as copies of 1 H and 13 C NMR spectra of all novel compounds.